Phenyl derivatives of methylsterols and process for production thereof



United States Patent 3,127,423 PHENYL DERIVATIVES 0F METHYLSTEROLS ANDPROCESS FOR PRODUCTION THEREOF Josef Fried, Princeton, and Gerald W.Krakower, Elizabeth, N.J., assignors to 01in Mathieson ChemicalCorporation, New York, N .Y., a corporation of Virginia No Drawing.Filed Sept. 21, 1962, Ser. No. 225,397

8 Claims. (Cl. 260-3971) This invention relates to and has as itsobjects the provision of new physiologically active steroids, methodsfor preparing the same, and new intermediates useful in saidpreparation.

The final products of this invention can be represented by the formulae:

m tgg wherein R is selected from the group consisting of hydrogen andthe acyl radical of a hydrocarbon carboxylic acid of less than tencarbon atoms; R' is selected from the group consisting of hydrogen andlower alkyl; and R is selected from the group consisting of hydrogen andhydroxy. (In this application and in the appended claims, whenever, inthe formulae set forth herein, a curved line (i) is employed in thelinkage of atoms, it is meant to denote that the connected atom may beeither in the alpha or beta position, as is determined in the respectivecompounds involved.)

The preferred acyl radicals are those of hydrocarbon carboxylic acids ofless than ten carbon atoms as exemplified by the lower alkanoic acids(e.g., acetic, propionic, butyric and tert-pentanoicacids), the loweralkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic andtoluic acids), the monocyclic aryl lower alkanoic acids (e.g.,phenacetic and B-pheny lpropionic acids), the cycloalkane carboxylicacids and the cycloalkene carboxylic acids.

The compounds of this invention are physiologically active steriodswhich possess anti-androgenic activity and which may be used in place ofsuch known anti-androgenic steroids as A-norprogesterone in thetreatment of such conditions as acne or hirsutism. Administration of theproducts of this invention may be accomplished either perorally orparenterally, in the same manner as A-norprogesterone, for example, thedosage and/or concentration being adjusted for the relative potency ofthe particular steroid.

The final products of this invention are prepared by the process of thisinvention which entails a number of steps beginning with a triterpenoidacid as a starting material. By a triterpenoid acid, it is here meant apolymethylsteroid, having a D-ring structure represented by the formula:

wherein R may be the same or different and may be either hydrogen oralkyl and R may be the same or different and may be selected from thegroup consisting of hydrogen and hydroxy. Examples of the triterpenoidacids which may be employed in the practice of this invention includeeburicoic, polyporenic, tumulosic, pinicolic, elemolic, elemonic,dehydroeburicoic, dehydroelemolic, dehydroelemonic, and other likeacids. The steps of the process (employing eburicoic acid as thestarting material) are shown by the following equations wherein R and Rare the same or different and represent hydrogen, lower alkyl, or acyl:

CH: HO C II i HO Eburicoic acid OH: R 00 C V R=H VI R=CHaO O VII VIIIR=CH2OO In the first step of the process of this invention, eburicoicacid is converted to its 3-ester derivative (Compounds A). The 3-acetateof eburicoic acid is a known compound. Other 3-esters can be prepared inthe usual manner by reacting eburicoic acid with the desired acylatingagent (e.g., acyl chloride or acid anhydride) in the presence of a base,such as pyridine. Although any ester can be thus prepared, the preferredesters are those with hydrocarbon carboxylic acids of less than tencarbon atoms. These are formed by reaction with the acyl chloride oracid anhydride of a hydrocarbon carboxylic acid of less than ten carbonatoms, such as one of the acids listed hereinbefore.

The 3-ester is then converted to the corresponding A eburicene esters(Compounds B). Compounds B are produced by first methylating theS-acetate esters, as by reaction with diazomethane in ether to producethe methylated 3-acetate ester of eburico-ic acid. The methylatedacetate ester is then treated with hydrogen in the presence of ahydrogenation catalyst to produce the A eburicene esters (Compounds B).

Compounds B are then treated with phenyl lithium, and held at anelevated temperature under a nitrogen blanket for an extended period oftime to yield the 21,21- diphenyl-A -cburicenes (Compounds C) which arenew compounds of this invention.

To form the final products of this invention the 21,21- diphenyl-A-eburicadienes (Compounds D) the 21,21- diphenyl-A -eburicenes(Compounds C) are dehydrated as by treatment at elevated temperatureswith glacial acetic acid or benzene and iodine, thus yielding CompoundsD which are new compounds of this invention.

In addition to the foregoing process, further steps may be employed toobtain further new products of this invention. The basic startingmaterial for this additional process may be the same triterpenoid acidemployed in the hereinbefore disclosed process, which starting materialis the source of the reactant employed in obtaining the additionalproducts of this invention. The following equations represent theprocess whereby the additional products are obtained; wherein R and Rare as hereinbefore defined, and R" represents hydrogen:

XVII R=CH3C O XVIII R=H In the first step of this alternate process,Compounds B are oxidized as by treatment with an oxidizing agent, forexample, chromic acid in an acetic acid medium to produce theM-eburicene-Zll-diones (Compounds E).

Compounds E are then reduced, as by treatment with zinc in glacialacetic acid, preferably at elevated temperatures to produce theeburicane-7g11-dliones (Compounds F).

Compounds F are then converted to the ll-keto-eburicanes (Compounds G)by treatment with hydrazine and a base, such as potassium hydroxide, atelevated temperatures. In addition to the reduction of the 7-keto group,there occurs hydrolysis of the ester groups at C and C and the latterare reformed by treatment first with an acylating agent (e.g., acidanhydride or ac-yl halide) in the presence of a base (e.g., pyridine)followed by treatment with a methylating agent (e.g., etherealdiazomethane), to produce Compounds G.

Compounds G are treated with lithium borohydr-ide in tetrahydrofuran toproduce the ll-hydroxyeburicanes (Compounds H). Compounds H are thentreated with methanesulfonyl chloride and pyridine in dimethylformamideto yield the A -eburicenes (Compounds J).

Compounds I may then be treated with phenyl lithium, and held at anelevated temperature under a nitrogen blanket for an extended period oftime to yield the 21,21- diphenyl-A -eburicenes (Compounds K) which arenew compounds of this invention.

Compounds K are then dehydrated as by treatment with glacial acetic acidat elevated temperatures, to yield the 21,2l diphenyl-A -eburicadienes,which are also new final products of this invention.

Still more new final products may be obtained from the additionalprocessing of Compounds G. These compounds are treated directly toobtain new final products t of this invention.

7 of this invention by the process set forth in the following equationswherein R, R and R" are as hereinbefore defined:

(G) XII R=oHa0o;R'=orn XIX R=H Compounds G are treated with phenyllithium and held at an elevated temperature under a nitrogen blanket'fOI an extended period of time to yield the1'1,21,21-tri-phenyleburicanes (Compounds M) which are new compoundsCompounds M are then dehydrated as by treatment with glacial acetic acidat elevated temperatures to yield the 11,21,21-triphenyl-A -eburicenes(Compounds N) which are new final products of this invention.

The procedures set forth hereinabove m the treatment -when tumulosicacid is treated in accordance with the procedures set forth hereinabove,the results represented by the following equations are obtained, R, Rand R" being the same as hereinbefore defined:

Tumulosic Acid CH1 ll R'OOC l --OR (AA) XXII R==OH3CO; R'=CH3 I ROOO I--OR (BB) xxnr R=eHBoo; R=OHa xxrv 3:11; R'=CH:

l --0R i no i i xxv R=c1nco XXVI R=H XXVII R=H XXVIII R=CH3CO under anitrogen blanket at elevated temperatures to yield the I6-substituted21,2l-diphenyl-A -eburicenes (Compounds CC) Which are new compounds ofthis invention.

Compounds CC may then be dehydrated as by treatment with glacial aceticacid at elevated temperatures to yield the16-substituted-2LZ1-diphenyl-A -eburicadienes (Compounds DD) which arealso new final products of this invention.

Similarly, as is true in the case of the processing of furtherderivatives of eburicoic add, new additional final products of thisinvention are obtained when the derivatives of tumulosic acid arelikewise processed according to the invention. The results obtained fromthis further processing may be represented by the following equations,wherein R, R and R" are as hereinbefore defined:

Row

Egg

ROOC I Row XXXV R=CHaCO XXXVI R=H XXXVII R=CH3CO XXXVIII 3:11

The processing of Compounds BB in accordance with the procedures setforth hereinabove for the processing of Compounds B through K, yieldsfurther new products of this invention, those being Compounds K and LL,corresponding to the products derived from the processing of eburicoicacid, to wit, Compounds K and L.

Still more corresponding new products are produced by further processingthe tumulosic acid derivatives, hereinbefore obtained. The results ofsuch further processing may be represented by the following equationswherein R, R' and R are as hereinbefore defined:

XXXIX 'n-cmoc v XL R=H CH, ll

I --OH Polyporenicacid 0 (DDD) XLVII R=CH CO XLVIII R=H (EEE) XLIX R=CHC O L R=H Polyporenic Acid C is first converted to a correpondingl6-ester of l6a-hydroxy-3-keto-A -eburicadiene-Zl-oic acid (CompoundsAAA) in the same manner as hereinbefore described in the treatment ofthe corresponding eburicoic acid.

Compounds AAA are then converted to the corresponding 2l-ester ofl6a-acetoxy-3-keto-A -eburicadiene- 2l-oic acid (Compounds BBB).Compounds BBB are then reduced as by treatment with sodium borohydrideand alcohol to yield the 3,16-dihydroxy-A -eburicadiene-Zl-oic acids(Compounds CCC). The 3,16- diacetyl-A -eburicadienes are obtained byacetylating Compounds CCC as by treatment with acetic anhydride inpyridine at room temperature.

Compounds CCC are then treated with phenyl lithium under a nitrogenblanket at elevated temperatures to yield the 21,2l-dipl1enyl-A'-eburicadienes (Compounds DDD) which are new compounds of thisinvention.

Compounds DDD are then dehydrated as by treatment with glacial aceticacid at elevated temperatures 14 to yield the 21,21-diphenyl1A-eburicatrienes (Compounds EEE) which are additional new final productsof this invention.

The following examples are illustrative of this invention (alltemperatures being in centigrade):

EXAMPLE 1 Acetyl-Eburicoz'c Acid (1) To a cooled solution of 500 g. ofeburicoic acid in 2.37 liters of pyridine 700 ml. of acetic anhydride isadded and the mixture allowed to stand overnight at room temperature.The excess acetic anhydride is decomposed by the addition of icefollowed by 4 liters of water. The precipitate of crude acetyl-eburicoicacid is collected and dissolved in 4 liters of chloroform. Thechloroform solution is washed with 5% hydrochloric acid, water and 5%potassium bicarbonate solution and the solution is then concentrated totwo liters. After the addition of 2 liters of methanol, the solution isreconcentrated to a volume of 2 liters and treated with decolorizingcharcoal. The solution is then concentrated and 419 g. of theacetyl-eburicoic acid (I) having a melting point of 240244, iscollected.

Following the procedure set forth in Example 1, but substitutingpropionic anhydride for acetic anhydride, yields propionyl eburicoicacid.

Similarly, by substituting other acid anhydn'des or acyl halides for thepropionic anhydride in the procedure of Example 1, the corresponding3-esters are formed. Thus, butyric anhydride and benzoyl chloride yieldbutyryl eburicoic acid and benzoyl eburicoic acid.

EXAMPLE 2 3,16-Diacetyl-Tumul0sic Acid Following the procedure ofExample 1, but substituting tumulosic acid for the eburicoic acid,3,16-diacetyl tumulosic acid, M.P. 227-228", is obtained.

EXAMPLE 3 Acetyl-Polyporenic Acid C Following the procedure of Example 1but substituting polyporenic acid C for the eburicoic acid,acetylpolyporenic acid C, M.P. 206-210", is obtained.

EXAMPLE 4 Mcthyl-Acetyl Eburicoate (II) To a suspension of 20 g. ofacetyl eburicoic acid (I) in 500 ml. of ether is added a solution ofdiazomethane in ether. The insoluble portion of the acid dissolves asthe reaction proceeds and after solution. is complete, diazomethane isadded until a yellow color persists. The excess diazomethane decomposedwith acetic acid, the solvent evaporated and the residue dried underhigh vacuum. The crude methyl ester on recrystallization frommethanol-chloroform gives a first crop of 15.40 g. methyl-acetyleburicoate (II), M.P. 153l54, and a second crop of 2.84 g., M.P. l51.

EXAMPLE 5 Methyl-3,16-Diacetyl Tumulosate (XXII) Following the procedureof Example 4 but substituting 3,16-diacetyl-tumulosic acid for theacetyl eburicoic acid, methyl-3,16-diacetyl tumulosate (XXII), M.P. 159159.5 is obtained.

EXAMPLE 6 Methyl Acctyl-Polyporenate C (XLIII) Following the procedureof Example 4 but substituting acetyl polyporenic acid C for acetyleburicoic acid yields methyl acetyl-polyporenate C (XLIII), M.P.122-124".

1 5 EXAMPLE 7 Methyl 3-Acetyl-M-Eburicenedfl-Ol-ZI-0ate (IV) A solutionof 85.0 g. of methyl 3-acetyl eburicoate (II) in 1.7 liters of ethylacetate, absorbs 1 equivalent of hydrogen when shaken in an atmosphereof hydrogen at room temperature and pressure in the presence of 5.1 g.of Adams catalyst. The catalyst is removed by filtration, the solventevaporated and the residue is recrystallized from 'methanol-chloroformto give a first crop of 69.8 g. of methyl 3-acetyl-A -eburicene-3,B-ol-21-oate (IV), M.P. l56159, and a second crop of 8.5 g., M.P. 153-154.

5.78, and 8.02

EXAMPLE 8 Methyl 3,16-Diacetyl-A -Eburicene-ifl,16a-Dil-21-0ate (XXIII)Following the procedure of Example 7 but substitutingmethyl-3,16-diacetyl tumulosate (XXII) for methyl-3- acetyl eburicoate(II), methyl 3,l6-diacetyl-A -eburicene 3;8,16oc-diol-2l-oate, M.P.,183-184, (XXIII) is obtained.

EXAMPLE9 Methyl 16-Acetyl-A -Eburicadiene-I6ot-0l-3-0ne- ZI-Oate (XLIV)Following the procedure of Example 7 but substituting methyl acetylpolyporenate (XLIII) for methyl acetyl eburicoate, yields methyl16-acetyl-A -eburicadiene- 16a-ol-3-one-21-oate (XLIV), M.P. 139-141.

EXAMPLE 10 Methyl 3-Acetyl-A -Eburicene-jfi-ol-Z]Z-Dione 21-Oate Asolution of 40 g. of chromic acid in 470 ml. of glacial acetic acid and30 ml. of water is added to 52.8 g. of methyl 3-acetyl-A-eburicene-3[3-ol-21-oate (IV) in 2.5 liters of glacial acetic acid,over a period of one hour, during which the temperature of the mixtureis maintained at 75 The temperature of the mixture is maintained at 75for an additional hour, at which time the excess chromic acid isdecomposed by the addition of 45 m1. of methanol. The reaction mixtureis concentrated on the rotary evaporator to approximately 200 ml. andafter dilution with 400 ml. of Water is extracted with chloroform. Thechloroform solution is washed with saturated aqueous sodium chloride,potassium bicarbonate and saturated aqueous sodium chloride andevaporated to dryness. The resultant crude orange semicrystallineproduct is dissolved in 100 ml. of hexane and 500 ml. of methanol andthe solution is concentrated until discernible crystallizationcommences. Orange, impure M-eburicene-Zll-dione (IX) is collected andredissolved in 200 ml. of benzene. 54 g. neutral alumina is added to thebenzene solution and after swirling for 5 minutes is removed byfiltration. The alumina is washed with 50 0 ml. of benzene and thecombined filtrates evaporated to yield 26.50 g. of a yellow crystallinematerial. Recrystallization from methanol gives 19.961

g. of the M-eburicene-Zll-dione (IX), M.P. 172-173;

k 270 m (e=8,600)

max.

Following the procedures set forth in Example but substituting methyl3,16-diacetylA -eburicene-3p,16o:- diol-Zl-oate (XXIII), formethyl-3-acetyl-A -eburicene- 3fi-ol-21-oate, yields methyl3,16-diacetyl-A -eburicene Nuial mill- 3,6,16ix-diol-7,11-dione-21-oate(XXIX) 16 EXAMPLE 12 Methyl 3-A cetyl-E buricane-3 [3-Ol-7,1 1-Di0ne-21-Oate (X) A solution of 55.6 g. of methyl 3-acetyl-Aeburicene-3fl-ol-7,11-dione-21-oate (IX) in 1.5 liters of glacial acetic acid isheated to reflux and 275 g. of granulated zinc (30 mesh) is added over aperiod of 15 minutes. After an additional 30 minutes, 75 g. of zinc dustis added. Heating of the mixture is continued until the total refluxtime from the start of the first addition equals 60 minutes. Thesolution is cooled and filtered and the acetic acid is evaporated invacuo. Recrystallization from methanol-chloroform gives a first crop of27.13 g. of methyl 3-acetyl-eburicane-3fi-ol-7,l1-dione-21-oate (X),M.P. 192-193; a second crop of 19.22 g. of (X), M.P. 191-192; and athird crop of 2.16 g. of (X), M.P. 188- 189;

REES 5.74, 5.83, 5.88;;

EXAMPLE 13 Methyl 3,16-Diacetyl-Eburicane-3/3,16aDiol-7,11-Dione-Zl-Oate (XXX) Following the procedure set forth in Example 12 butsubstituting methyl 3,16-diacetyl-A -eburicene-3 8,16adiol-7,ll-dione2l-oate (XXIX), for methyl-3-acetyl-M- eburicene-3fl-ol-7,1l-dione21-oate, yields methyl 3,16- diacetyl eburicane 36,16ot diol 7,11dione-21-oate (XXX).

EXAMPLE 14 Methyl 3-A cetyl E buricane-3 fl-Ol-l 1 -0 ne-21 -0ate (XI) Asolution of 150 mg. of methyl 3-acetyl-eburicane-35-ol-7,11-dione-21-oate (X) in 25 ml. of diethylene glycol containing0.5 ml. of hydrazine hydrate is heated at reflux for 2 hours. Aftercooling, 3 g. of

potassium hydroxide in 5 ml. of diethylene glycol is added and thetemperature of the solution is raised to 195 by distilling off water andhydrazine. The temperature of the solution is maintained at 195 for 4hours, after which it is cooled. The cooled reaction mixture is pouredinto ml. of 3 N hydrochloric acid and extracted with ether andchloroform The combined organic layer is washed with water, dried oversodium sulfate and evaporated. The crude product is reacetylated withacetic anhydride in pyridine at room temperature, remethylated bytreatment with ethereal diazomethane and then chromatographed on 4 g. ofneutral alumina. The benzene-chloroform eluates are recrystallized frommethanol to give 9 mg. of methyl 3-acetyl-eburicane-Iifi-ol-l1-one-21-oate (XI), M.P. 156.

Nuiol Analysis.Calcd. for C H O C, 74.95; H, 10.36. Found: C, 74.54; H,10.17.

EXAMPLE 15 Methyl 3,16-Diacetyl-Eburbane-35,16e-Di0l-H-One-21- Oate(XXXI) Following the procedure set forth in Example 14, but substitutingmethyl 3,16-diacetyl-eburicane-3,B,l6a-diol- 7,11-dione-21-oate (XXX),for methyl 3-acetyl-eburicane- 3,B-ol-7,11-dione-21-oate, yields methyl3,16-diacetyleburicane-3fl,16a-diol-11-one-21-oate (XXXI) EXAMPLE 16Methyl 3-A celyl-Eburicane-3fi,1 Z/EI-Diol-ZI-Oate (XIII)Analysis.Calcd. for C H O C, 74.68; H, 10.69; OCH 5.67. Found: C, 74.64;H, 10.21; OCH 5.01.

EXAMPLE 17 Methyl 3,16-Diacetyl-Eburicane-EIBJ1,8,16u-Tril-21 Oate(XXXIII) Following the procedure set forth in Example 16 butsubstituting methyl 3,16-diacetyl-eburicane-3/3,16ot-diol-1l-one-21-oate (XXXI) for methyl 3-acetyl-eburicane-3/i- 01-11-one-2l-oate yields methyl 3,16-diacetyl-eburicane- 35,1113,1611-(1'101-2 l-oate (X)Q(III).

EXAMPLE 18 Methyl 3-Acetyl-A -Eburicane-3,8-Ol-2I-Oate (XIV) To asolution of 15 mg. of methyl 3-acetyl-eburicane- 35,11,8-diol-21-oate(XIII) in 1 ml. of dimethylformamide is added 0.1 ml. of pyridine and0.05 ml. of methanesulfonyl chloride and the mixture is held at roomtemperature for 18 hours. Water is added and the reaction mixture isextracted with chloroform. The chloroform layer is washed with water,dried over magnesium sulfate and evaporated. Recrystallization of thecrude product from methanol yields 8 mg. of analytically pure methyl3-acetyl-A -eburicene-3,8-ol-21-oate (XIV) having the followingproperties: M.P. 154-155 [a] +62.0 (chlf. C., 0.66); and a second cropof 4 mg. of (XV) having an M.P. of 150-152.

max.

Analysis.Calcd. for C H O C, 77.22; H, 10.67. Found: C, 77.52; H, 10.93.

EXAMPLE 19 Following the procedure set forth in Example 18 butsubstituting methyl 3,16-diacetyl-eburicane-3fi,11fi,l6atriol-21-oate(XXXIII) for methyl 3-acetyl-eburicane-3fi; llfl-diol-Zl-oate yieldsmethyl 3,l6-diacetyl-A -eburicene-3,B,16ot-diol-21-oate (XXXIV) EXAMPLE20 Methyl A -Eburicene-SB-OI-ZI-Oate (III) A solution of 500 mg. ofmethyl 3-acetyl-A -eburicene 3fi-ol-21-oate (IV) in 200 ml. of l Nethanolic potassium hydroxide is allowed to stand at room temperaturefor 16 hours. The solution is then neutralized with 20% sulfuric acidand the solids filtered. The filtrate is diluted with water and theethanol evaporated. The resulting solids are combined with thepreviously collected material and partitioned between ether and water.The ether layer is washed with Water and evaporated to give 484 mg. ofmethyl A -eburicene-3B-ol-2l-oate (V), which is then recrystallized frommethanol to yield 284 mg. of crystalline material having a melting pointof 139444";

EXAMPLE 21 Methyl A -Eburz'cene-ifiiJ6et-Di0l-21-0ate (XXIV) Followingthe procedure of Example 20, but substituting methyl 3,16-diacety1-A-eburicene-3/3,l6ot-diol-21-oate (XXIII) for methyl 3-acetyl-A-eburicene-3,8-ol-2l-oate, yields methyl A-eburicene-3/3,l6a-dio1-21-oate (XXIV).

EXAMPLE 22 Methyl A' -Eburicadiene-16a-Ol-3-One-21-Oate Following theprocedure set forth in Example 20, but

18 substituting methyl 16aCetyl-A -6bl11'l3d16l16-1fiat-(i1-3-one-21-oate (XLIV) for methyl 3-acetylA -eburicene- 3,8-ol-21-oate(IV) yields methyl A' -eburicadiene 16tX-Ol-3-OI1C-21-O3t3.

EXAMPLE 23 Methyl A -Eburicadiene-3 {3,1 6a-Di0l-21 -Oate (XLVI) Asolution of methyl A -eburicadiene-16ot-ol-3-one- 21-oate in dioxane, istreated with sodium borohydride in aqueous dioxane for one hour at roomtemperature. Acidification of the mixture with 5% hydrochloric acid andextraction with ether yields a crude product, which afterrecrystallization from methanol-chloroform, gives methyl A-eburicadiene-SB,16a-diol-2l-oate (XLVI).

EXAMPLE 24 Methyl 3,16-Diacetyl-A -Eburicadiene-3BJ6a-Di0l- 210m (XLV)Methyl A' -eburicadiene 3,3, 16a diol 21 oate (XLIV) is treated with asolution of acetic anhydride in pyridine containing 2.1 mole equivalentsof acetic anhydride at room temperature for eighteen hours. The reagentsare evaporated in vacuo and the crystalline residue is recrystallizedfrom methanol. After two crystallizations, methyl 3,16-diacetyl-A'-eburicadiene-3 3,- 16ot-dio1-2l-oate (XLV) is obtained.

EXAMPLE 25 21,21-Diphenyl-M-Eburlcene-SQZI-Di0l (V) A solution of 3mmole of phenyl lithium in 3 ml. of ether is added to a solution of 243mg. of methyl A eburicene-3B-ol-21-oate (III) (0.5 mmole) in 20 ml. ofdry benzene. The mixture is heated at reflux under nitrogen for 18hours, during which time a copious precipitate develops. The cooledreaction mixture is then acidified with 5 ml. of 20% sulfuric acid, andthe aqueous layer separated and washed with benzene. The combinedorganic solution is Washed with water until neutral, dried overmagnesium sulfate and evaporated to give 378 mg. of crude21,21-diphenyl-A -eburicene-3,8,2l-diol (V).

EXAMPLE 26 21,21-Diphenyl-A -Eburicene-3pJ6a,21-Tri0l (XXVI) Followingthe procedure set forth in Example 25, but substituting methyl A-eburicene 35,160: diol-2l-oate (XXIV) for the methyl A-eburicene-3/3-ol-2l-oate (HI) yields 21,21 diphenyl -A eburicene 35,16oz, 21 triol (XXVI).

EXAMPLE 27 Following the procedure set forth in Example 25 butsubstituting methyl A' -eburicadiene-3}3,l6a-diol-2loate (XLVI) formethyl A -eburicene-3/3-o1-2l-oate (HI) yields 21,2 l-diphenyl-A-eburicadiene-3/3, l 6et,2l-triol (XLVIII).

EXAMPLE 28 2],2]-Diphenyl-A Eburicadiene-3fl-Ol (VII) The21,21-diphenyl-A -eburicene35,2l-diol (V) obtained in Example 25 isdehydrated by the addition or 5 ml. of glacial acetic acid and is heatedat reflux for one hour to yield the crude 21,21-diphenyl-A-eburicadiene-3/3-ol (VII).

EXAMPLE 29 21,21-DiphenylA -Eburicadiene-3fl,I6a-Di0l (XXVII) Followingthe procedure set forth in Example 28 but substituting 21,2l-diphenyl-A-eburicene 3B,l6a,21 triol (XXVI) for 21,21-diphenyl-A-eburicene-3fl,2l-diol (V) yields 21,21 diphenyl A eburicadiene 318,160;diol (XXVII).

1% EXA irLn 30 Following the procedure set forth in Example 28 butsubstituting 21,21-diphenyl-A eburicadiene 35,16a, 21-triol (XLVIII) for21,21-diphenyl-A -eburicene-33,21- diol (VII), yields 21,2l-diphenyl-A-eburicatriene- 3fi,l6adi0l (L).

EXAMPLE 31 3-Acetyl-21,21-Diphenyl-A -Eburicadiene-Sfi-Ol (VIII) I 248mu (e=12,500)

Fractions 51-66 (benzene) give on recrystallization 31 mg. of3-acetyl-21,21-diphenyl-A -eburicadiene 3B o1 (VIII), M.P. 178-l8 Thesample recrystallized for analysis has M.P. 189- 190.

x55; 514 5.35,, 5.55 (weak), 5.75 6.24 13.18 1 1.27

Analysis.Calcd. for C H O C, 85.12; H, 9.84. Found: C, 84.37, 84.41; H,9.55, 9.11.

EXAMPLE 3 2 3,16-Diacetyl-21,21-Diphenyl-A -Eburicadiene-3B,16on- Diol(XXVIII) Following the procedure set forth in Example 31, butsubstituting the 2l,21-diphenyl-A -eburicadiene-3B,16adiol obtained inExample 29 for 21,21-diphenyl-A eburicadiene-3fi-ol (VII) yields3,16-diacetyl-21,2l-diphenyl-A -eburicadiene-3fl,16a-diol (XXVIII)EXAMPLE 3 3 3,16-Diacetyl-21,21 -Diphenyl-A -EbIIri0atriene-3fi,16a-Diol (XLIX) Following the procedure set forth in Example 31, butsubstituting the 21,21-diphenyl-A -eburicatriene-3fi, 16a-diol, obtainedin Example 30 for 21,21-diphenyl-A eburicadiene-3fl-ol (VII) yields 3,l6-diacetyl-2l,2l-diphenyl-A -eburicatriene-3B, 1 fill-diol (XLIX)EXAMPLE 34 3-Acetyl-21,21-Diphenyl-M-Eburicened/LZI-Di0l (VI) A solutionof 15 ml. of phenyl lithium in ether (6.0 mmole) is added to 528 mg. ofmethyl 3-acetyl-A eburicene-3/3-ol-21-oate (III) (1 mmole) in 40 ml. ofdry benzene. After 3 hours at room temperature, the reaction mixture isacidified with 20 ml. of hydrochloric acid and 20 ml. of ether is added.The organic layer is separated, washed with 5% hydrochloric acid andWater and evaporated. The residue is then acetylated by treatment withpyridine and acetic anhydride at room temperature to give 979 mg. ofcrude 3-acetyl-21,21-diphenyl-A -eburicene-3fi,2l-diol (VI).

EXAMPLE 3 5 3,16-Diacetyl-2],21-Diphenyl-A -Eburicene-3B,16a,21- T riol(XXV) Following the procedure set forth in Example 34, but substitutingmethyl 3,16-diacetyl-A -eburicene-3 8,16u-diol- 21-oate (XXIII) for themethyl 3-acetyl-A -eburicene-3fiol-2l-oate (III), yields3,16-diacety1-21,21-diphenyl-A eburicene-3B,16a,21-triol (XXV) 20EXAMPLE 36 3,16-Diacetyl-21,21 -Dz'plzenyl-A -Eburicadienedfl,16a,21-Tri0l (XLVII) Following the procedure set forth in Example 34,but substituting methyl-3,16-diacetyl-A' -eburicadiene 3B,l6a-diol-21-oate (XLV) for methyl 3-acetyl-A -eburicene- 3fi-ol-21-oate(III) yields 3,16-diacetyl-21,21-diphenyl- A-eburicadiene-3fl,l6a-21-triol (XLVII).

EXAMPLE 37 3-Acetyl-2],21-Diphenyl-A -Eburicadiene-iB-Ol (VIII) 492 mg.of 3-acet'yl-21,21-diphenyl-A -ebnricene-313,21- diol (VI) obtained inExample 34 is dissolved in benzene containing a few crystals of iodineand dehydrated by distillation of benzene. After 50 ml. of distillateare collected, the remaining solution is washed with sodium thiosulfatesolution and water, and evaporated to give 444 mg. of3-acetyl-21,21-diphenyl-A -eburicadiene-Bfl- 01 (VIII). Chromatographyon 27 g. of neutral alumina and elution with benzene gives, afterrecrystallization from methanol, 81 mg. of 3-acetyl-21,21-diphenyl-Aeburicadiene-Bfl-ol (VIII), M.P. 186-188;

A532, 248 m/L (e 12,600)

EXAMPLE 38 3-A cetyl-Zl ,21-Diphenyl-A -Eburicadiene jfl ol (VIII) 468mg. of crude 3-acetyl-21,2l-diphenyl-A -eburicene- 35,21-di0l (VI)obtained in Example 34 is dehydrated by refluxing a solution in 5 ml. ofglacial acetic acid for 1 hour. After evaporation of the acetic acid,the residue is chromatographed on 27 g. of neutral alumina. Elution withhexane-benzene (1:1) yields after recrystallization from methanol 43 mg.of 3-acetyl-2l,21-diphenyl-A eburicadiene-3fi-ol (VIII), M.P. 178-182".

EXAMPLE 39 3-A cetyl-21,21-Diphenyl-A -Eburicadiene-3fi-Ol (XVII) Asolution of 10 ml. of phenyl lithium in ether (4.2 mmole) is added to329 mg. of methyl 3-acetyl-eburicane- 33,11/8-diol-21-oate (XIII) (0.6mmole) in 25 ml. of dry benzene and is left at room temperature for 3hours. After addition of 20 ml. of 5% hydrochloric acid, the organicphase is separated, washed with water and evaporated.

The residue is heated at reflux with 5 ml. of glacial acetic acid for 1hour in order to dehydrate and then is reacetylated by treatment withpyridine and acetic anhydride at room temperature to give 425 mg. ofcrude 3- acetyl-Zl,21-diphenyl-A -eburicadiene-3fi-ol (XVII).Chromatography of the crude product on 25 g. of neutral alumina, elutionwith benzene and recrystallization from methanol yields 149 mg. of3-acetyl-21,2l-diphenyl- A -eburicadiene-3fl-ol (XVII), M.P. l79l82 and26 mg. of (XVII), M.P. 176-177.

The analytical sample melts at 182-183 A 247 mp (e=13,400)

max.

Analysis.Calcd. for C H O C, 85.12; H, 9.84. Found: C, 84.98; H, 9.71.

A solution of 10 ml. of phenyl lithium in ether (4.2

21 mmole) is added to 300 mg. of methyl S-acetyl-eburicane-35,11fi-diol-21-oate (XIII) in 25 ml. of dry benzene and is left at roomtemperature for 3 hours. After addition of 20 ml. of 5% hydrochloricacid, the organic phase is separated, Washed with water and evaporated.

The residue is then reacetylated with pyridine and acetic anhydride atroom temperature and is treated in accordance with the procedure setforth in Example 37 to yield 52 mg. of 3-acetyl-21,21-diphenyl-A-eburicadiene-3fl-ol (XVII), M.P. 183-184";

EXAMPLE 42 21,21-Diphenyl-A -Eburicene-3[3,21-Di0l (XV) A solution of264 mg. of methyl 3-acety1-A -eburicene-3;3-ol-2l-oate (XIV) (0.5 mmole)in 20 ml. of dry benzene containing 6.2 ml. of phenyl lithium in ether(2.5 mmole) is kept at room temperature for 3 hours. After addition of20 ml. of 5% hydrochloric acid and separation of the organic layer, theaqueous layer is extracted with ether and the combined organic layersWashed with water and evaporated, to yield the crude 2l,21-diphenyl-A-eburicene-3/8,21-diol (XV).

max.

EXAMPLE 43 21,2]-Diphenyl-A -Eburicene-3B,16a,21-Tri0l (XXXVI) Followingthe procedure set forth in Example 42 but substituting methyl3,16-diacetyl-A -eburicene-iior,16stdiol-21-oate (XXXIV) for methyl3-acetyl-A -eburicene-3B-'ol-21-oate (XIV) yields 21,21-diphenyl-Aeburicene-Bfi,16a,2l-triol (XXXVI).

EXAMPLE 44 3-Acetyl-Z1,21-Diphenyl-A -Eburicadiene-3fi-0l (XVII) The21,21-diphenyl-A -eburicene-3/3,2l-diol (XV) obtained in Example 42 isacetylated by treatment with pyridine and acetic anhydride at roomtemperature and the crude acetylation product obtained is thendehydrated according to the procedures set forth in Example 39 to give329 mg. of crude 3-acetyl-21,21-diphenyl-A eburicadiene-3fi-ol (XVII).Chromatography on 20 g. of neutral alumina, elution with benzene andrecrystallization from methanol yields 110 mg. of3-acetyl-2l,2l-diphenyl-A -eburicadiene-Elfl-ol (XVII), M.P. 180- 181(softening at 175);

A593? 248 my. ($14,300)

and a second crop of 8 mg. of XVII, M.P. 175-178".

EXAMPLE 45 3,1 6-Diacetyl-21,21-Diphenyl-A -Eburicadiene-3B, loot-Dial(XXXVII) Following the procedure set forth in Example 44 butsubstituting the 21,2l-diphenyl-A -eburicene-3fi,16a,2ltriol (XXXVI)obtained in Example 42 for 21,21-dipheny1-A -eburicene-3;3,2l-diol (XV),yields 3,16-diacetyl 21,21 diphenyl-A -eburicadiene-3/8,16a-di0l(XXXVII).

EXAMPLE 46 Methyl Eburicane-iB-Ol-J]-ne 21-Oate (XII) A solution of 2.0g. of methyl 3-acetyl-eburicane-3/8-ol- 1l-one-21-oate (XI) in 400 ml.of 1 N ethanolic potas sium hydroxide is allowed to stand at roomtemperature for 18 hours. The solution is then neutralized with 20%sulfuric acid, diluted with water and the ethanol evaporated. Theaqueous suspension is then extracted with ether and the ether solutionwashed with Water, dried over magnesium sulfate and evaporated.Recrystallization from methanol yields 1.55 g. of methyl eburicane- 223fi-oi-l1-one-21-oate (XII), M.P. 133435". lytical samples melt at137-l39;

RR? 2.97, 5.77, 5.89 Analysis.Calcd. for C H O C, 76.44; H, 10.83.

Found: C, 76.14; H, 10.63.

EXAMPLE 47 Methyl Eburicane-3/3J 60c-Dl'0l-11-OH6-2I-O6lt6 (XXXII)Following the procedure set forth in Example 46, but substituting methyl3,16-diacetyl-eburicane-3fl,16a-diol- 11-one-21-oate (XXXI), for methylB-acetyl-eburicane 3,8-ol-11-one-21-oate, yields methyleburicane-3B,16a-diol 11one-21-oate (XXXII).

EXAMPLE 48 11 ,2] ,2] -Trz'phenyl-Eburicane-3p,1 1,8,21 -Trz'0l (XIX) Asolution of 251 mg. of methyl eburicane-3fi-ol-11- one2l-oate (XII),(0.5 mmole) in 25 ml. of dry benzene containing 4 m1. of phenyl lithiumin ether (2.0 mmole) is held at room temperature for 20 hours. Anadditional 4 ml. of phenyl lithium in ether is added and the reactionmixture kept at room temperature for an additional 20 hours. Afteraddition of 25 ml. of 5% hydrochloric acid, the organic layer isseparated, washed with water and evaporated to yield the crude11,21,21-triphenyleburicane-3 3,1lB,21-triol (XIX).

EXAMPLE 49 11,2],21-Triphenyl-Eburbane-35,115,16a,21-Telra0l Followingthe procedure set forth in Example 48 but substituting methyleburicane-3B,16u-diol-1l-one-21-oate (XXXII) for methyleburicane-3/3-ol-1l-one'2l-oate (XII) yieldsl1,21,2l-triphenyl-eburicane-3B,llp,l6a,2ltetraol (XL).

The ana- EXAMPLE 50- 3-Acetyl-1 1,21 ,21 -Tri phenyl-A -E buricene-3 9,11 fl-Diol (XXI) W 2.ss,., 5.16,., 5.35,., 5.55 5.82 6.26 13.15

max.

The analytical sample has a M.P. 172.5-l73;

A 237 m (e=10,000)

Analysis.Calcd. for C H O C, 84.01; H, 9.40. Found: C, 83.97; H, 10.01.

EXAMPLE 51 3,]6-Diacetyl-11,21,2]-Triphenyl-A -Eburicene- 3 ,115,16a-Tri0l (XLI) Following the procedure set forth in Example 50 butsubstituting the crude 11,21,21-triphenyl-eburicane-3 B, 115,2l-tetrol(XL) obtained in Example 48 for 11,21,21-triphenyl-eburicane-3B,115,21-triol (XIX) yields 3,16- diacetyl 11,21,21triphenyl-A -eburicene 318,115,16atriol (XLI).

EXAMPLE 52 11,21,2]-Triphenyl-A -Eburicene-3;S,1LB-Diol (XX) Followingthe procedure set forth in Example 46 but 23 substituting 3-acety1-11,21,21-triphenyl-A -eburicene-3[3, 11 fi-diol (XXI) formethyl-3-acetyl-eburicane-3 8-01-llone-Zl-oate (XII) yields11,21,21-triphenyl-A -eburicene-BflJIfl-diol (XX), a non-crystallinematerial whose infrared spectrum showed no adsorption in the carbonylregion 5.5-6.0

EXAMPLE 53 Following the procedure set forth in Example 46, butsubstituting 3,16 diacetyl 11,21,21 triphenyl-A -ebu'ricene-3 3,llli,l6a-triol (XLI) for methyl 3-acetyl-eburicane-3/3-ol-11-one-21-oate(XII) yields 11,21,21-tripheny1-A -eburicene-3fi,11/8,16a-trio1 (XLII)EXAMPLE 54 3-Acetyl-1],21,21 -Triphenyl-Eburicane-jflJ 1fl,21-Tri0lFollowing the procedure of Example 1, but substituting11,21,2l-triphenyl-eburicane 35,11,831 triol (XIX) for eburicoic acidyields 3-acety1-11,21,21-triphenyl-eburicane-313,1 1,9,21-triol.

EXAMPLE 55 3 ,1 6-Diacetyl-1 I ,2] ,2] -T riphenyl-Eburicane-35,11B,16a,21-Tetral (XXXIX) Following the procedure of Example 1, butsubstituting 11,21,2l-triphenyl-eburicane 3,8,11fl,l6a,21 tetrol (XL)for eburicoic acid yields 3,16-diacetyl-11,21,21-triphenyleburicane-38,11B,16a,21 tetraol (XXXIX) EXAMPLE 56 3,16-Diacetyl-21,2I-Diphenyl-A-Eburicadiene- 3/3,]6a-Di0l (XXVIII) Following the procedure set forthin Example 28 but substituting 3,16-diacetyl-21,21-diphenyl-A-eburicene-3B, 16u,21-triol (XXV) for 21,21-diphenyl-A -eburicene-3B,2-1-diol yields 3,l6-diacety1-21,21-diphenyl-A-eburicadiene-3fi,16a-diol.

EXAMPLE 57 3,16-Diacetyl-21,21-Diphenyl-A -Eburicatriene- 3,6,16a-Diol(XLIX) Following the procedure set forth in Example 28 but substituting3,16-diacetyl-21,21 diphenyl-A' -eburicadiene-3B,16u,21-triol for21,21-diphenyl-A -eburicene-35, 21 diol yields 3,16 diacetyl21,21-diphenyl-A eburicatriene-3B,l6a-diol.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of steroids having theformulae wherein R is selected from the group consisting of hydrogen andthe acyl radical of a hydrocarbon carboxylic acid of less than tencarbon atoms; R is selected from the group consisting of hydrogen andlower alkyl; and R is selected from the group consisting of hydrogen,hydroxy and acyloxy, wherein the acyl radical is of a hydrocarboncarboxylic acid of less than ten carbon atoms.

2. A compound selected from the group consisting of steroids having theformulae:

"E? 25MB Q wherein R' is selected from the group consisting of hydrogenand the acyl radical of a hydrocarbon carboxylic acid of less than tencarbon atoms; R is selected from the group consisting of hydrogen andlower alkyl; and R is selected from the group consisting of hydrogen,hydroxy and acyloXy, wherein the acyl radical is of a hydrocarboncarboxylic acid of less than ten carbon atoms.

3. A compound selected from the group of steroids consisting of3-acyloxy-21,21-diphenyl-A -eburicene-21-ol; 3-acyloxy-21,21-diphenyl-A-eburicene 21 01; and 3- acyloxy-l 1,21,2l-triphenyl-eburicane-l113,21-dio1.

4. A compound selected from the group of steroids consisting of 21,21diphenyl A eburicene-3[3,2l-diol; 21,21-diphenyl-A-eburicene-3/S,2l-diol; and 11,21,21- triphenyl-eburicane-3 5,116,21-triol.

5. A compound selected from the group of steroids consisting of3-acyloxy-21,21-diphenyl-A -eburicadiene; 3-acyloxy 21,21 diphenyl-A-eburicadiene; and 3- acyloxy-l 1,21,21-triphenyl-A -eburicene-1 113-01.

6. A compound selected from the group of steroids consisting of21,2l-dipheny1-A -eburicadiene 3/3 o1; 21,2l-diphenyl-A-eburicadiene-35-01; and 11,21,21- triphenyl-A -3 {3,1 1 fi-diol.

7. The process for preparing a compound of claim 1 which comprisesdehydrating a corresponding compound of claim 2 by treatment with heatand a dehydrating agent selected from the group consisting; of benzeneand iodine and glacial acetic acid.

8. The process of producing a compound of claim 2, which comprisesreacting a corresponding compound selected from the group of steroidshaving the formulae:

wherein Z is lower alkyl; R is selected from the group consisting ofhydrogen, hydroxy and acyloxy, wherein the acyl radical is from ahydrocarbon carboxylic acid of less than ten carbon atoms; R'" isselected from the group consisting of hydrogen and lower alkyl; R isselected from the group consisting of hydrogen and the acyl radical of ahydrocarbon carboxylic acid of less than ten carbon atoms; each R and R'is selected from the group consisting of hydrogen and hydroxy; andtogether R" and R' is oxo; with a phenyl lithium.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,127,423 March 31, 1964 Josef Fried et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 9, lines 1 to 20, t'hefirst formula should appear as shown belowinstead of as in the patent:

XXVII R=H XXVIII R=CH3CO same column 9, lines 60 to 75 the third formulashould appear as shown below instead of as in the patent:

(EB) XXIX R=CH3CO; R=CH3 column 10, line 14, for "R=CH CO; R=CH read XXXR= CH CO; R =CH line 27 for "XXXI R=CH CO; R =CH read XXXI R=CH CO; R=CH column 13, line 15 for "XLVI R=H:R=CH read XLVI R=H; R=CH column 21,line'60, for "Example 42" read Example '43 column 22 line 59 for "237mu" read 247 mp Signed and sealed this 13th day of October 1964.

(SEAL) Attest;

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS HAVING THEFORMULAE